ER-PM Contact Sites - SNARING Actors in Emerging Functions

Abstract

The compartmentalisation achieved by confining cytoplasm into membrane-enclosed organelles in eukaryotic cells is essential for maintaining vital functions including ATP production, synthetic and degradative pathways. While intracellular organelles are highly specialised in these functions, the restricting membranes also impede exchange of molecules responsible for the synchronised and responsive cellular activities. The initial identification of contact sites between the ER and plasma membrane (PM) provided a potential candidate structure for communication between organelles without mixing by fusion. Over the past decades, research has revealed a far broader picture of the events. Membrane contact sites (MCSs) have been recognized as increasingly important actors in cell differentiation, plasticity and maintenance, and, upon dysfunction, responsible for pathological conditions such as cancer and neurodegenerative diseases. Present in multiple organelles and cell types, MCSs promote transport of lipids and Ca²⁺ homoeostasis, with a range of associated protein families. Interestingly, each MCS displays a unique molecular signature, adapted to organelle functions. This review will explore the literature describing the molecular components and interactions taking place at ER-PM contact sites, their functions, and implications in eukaryotic cells, particularly neurons, with emphasis on lipid transfer proteins and emerging function of SNAREs.

Keywords: SNAREs; lipid transfer; membrane contact sites; neurons; tethers.

FIGURE 1

Schematic illustration of the organization and topology of ER-PM tethering proteins. Shown are the so-far identified protein complexes acting in ER to PM membrane recruitment, in yeast and mammals: Sec22b-Syntaxin1/3 (Sso1/2p in yeast) complex, TMEM16 (Ist2 in Yeast), TMEM24 (C2CD2L in Yeast), Kv Channels, Junctophillins, VAPs (Sc2-22 in Yeast), Extended Synaptotagmin (E-Syt). SNARE complexes generate short-range (∼10 nm) MCS whereas other tethers generate longer range (∼20–30 nm). Created with BioRender.com.

FIGURE 2

SNAREs and lipid transfer proteins at the MCS. Using varying mechanisms such as FFAT to bridge SNAP25-OSH/ORP-VAP-A, and non-fusogenic Sec22b-Stx1- E-Syt complex, LTPs promote MCS tethering and mediate lipid transfer [PI4P, sterol, glycerolipids, and diacylglycerol (DAG)]. PI4P phosphatase at the ER membrane Sac1 was not represented for simplicity. Created with BioRender.com.

FIGURE 3

Ca²⁺ influx at the ER-PM contact site. Tethering proteins involved in the control of the Ca²⁺ ions fluxes between the ER lumen, the cytosol and the extracellular medium: ORA1, STIM1, SERCA, and IP3 Receptor (IP3R). IP3R is activated by IP3 generated by Phospholipase C (PLC) upon activation of G-protein coupled receptor (GPCR). The G protein subunits ware not represented for simplicity. Created with BioRender.com.